tbuckley/cabot-search huggingface dataset:
Does autonomous macrophage-driven inflammation promote alveolar damage in COVID-19?
Authors: David H. Dockrell, Clark D. Russell, Brian McHugh, Rupsha Fraser
Journal: European Respiratory Journal (2022)

<b>The editorial reviews an <i>ERJ</i> publication which shows direct viral replication is rare in the alveolar space due to rare ACE2 expression. Instead it posits that autonomous macrophage inflammation occurs and drives lung injury.</b>https://bit.ly/3CqjwiT
Measuring intra-subject changes in respiratory mechanics by oscillometry: impedance <i>versus</i> admittance
Authors: Ramon Farré
Journal: European Respiratory Journal (2022)

Recent state-of-the-art reviews [1, 2] and research [3] have pointed out the potential interest of oscillometry for noninvasively characterising lung mechanics from the relationship between oscillatory pressure ( P ) and flow ( V′ ) at different frequencies. Two magnitudes have usually represented this relationship: resistance ( R ) and reactance ( X ), which are the real and imaginary parts of respiratory impedance ( Z=R+j·X ). Clinical [1, 2] and modelling data [4] show that both R and X depend on the interaction between resistances and compliances of central and peripheral airways and lung tissues. Even at the low oscillometry frequency of 5 Hz (which is a critical reference frequency for clinical studies [1, 2]), a simple interpretation of R and X is not possible [4]. Measuring intra-subject changes in respiratory mechanics by oscillometry may be optimised by using respiratory admittance instead of impedance <https://bit.ly/3T2WeWb>
2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension
Authors: Marc Humbert, Gabor Kovacs, Marius M. Hoeper, Roberto Badagliacca, Rolf M.F. Berger, Margarita Brida, Jørn Carlsen, Andrew J.S. Coats, Pilar Escribano-Subias, Pisana Ferrari, Diogenes S. Ferreira, Hossein Ardeschir Ghofrani, George Giannakoulas, David G. Kiely, Eckhard Mayer, Gergely Meszaros, Blin Nagavci, Karen M. Olsson, Joanna Pepke-Zaba, Jennifer K. Quint, Göran Rådegran, Gerald Simonneau, Olivier Sitbon, Thomy Tonia, Mark Toshner, Jean-Luc Vachiery, Anton Vonk Noordegraaf, Marion Delcroix, Stephan Rosenkranz
Journal: European Respiratory Journal (2022)

2022 ESC/ERS pulmonary hypertension guidelines incorporate changes and adaptations focusing on clinical management https://bit.ly/3QtUvb4
Retrospective comparison of survival and responses to Fludarabine, Cytarabine, <scp>GCSF</scp> (<scp>FLAG</scp>) in combination with gemtuzumab ozogamicin (<scp>GO</scp>) or Idarubicin (<scp>IDA</scp>) in patients with newly diagnosed core binding factor (<scp>CBF</scp>) acute myelogenous leukemia: <scp>MD</scp> Anderson experience in 174 patients
Authors: Gautam Borthakur, Farhad Ravandi, Keyur Patel, Xuemei Wang, Tapan Kadia, Courtney DiNardo, Guillermo Garcia‐Manero, Naveen Pemmaraju, Elias J. Jabbour, Koichi Takahashi, Maro Ohanian, Naval Daver, Yesid Alvarado, Mark Brandt, Sherry Pierce, Hagop Kantarjian
Journal: American Journal of Hematology (2022)

Fludarabine, cytarabine, GCSF (FLAG)-based induction/consolidation results in high remission rates in core binding factor (CBF) acute myelogenous leukemia. We treated 174 consecutive patients with newly diagnosed CBF-AML in a prospective clinical trial of FLAG-based induction/consolidation in combination with gemtuzumab ozogamicin (FLAG-GO; N = 65) or in combination with idarubicin (FLAG-IDA; N = 109). The 5 year RFS in the FLAG-GO cohort was significantly better than the FLAG-IDA cohort, 78% versus 59%, respectively (p-value = .02). In multivariate analysis for RFS, age (p = .0001), FLAG-GO regimen (p = .04), 4 log reduction in CBF-related fusion transcript by quantitative polymerase chain reaction (qPCR) in bone marrow samples at end of consolidation therapy (p = .03), and additional cytogenetic abnormalities (p = .03) were significant variables. Lower age (p = .0001) and 3 log or more transcript reduction at end of induction (p = .04) were significant variables predicting for better overall survival (OS), while there was strong trend for better OS with FLAG-GO (p = .06) regimen. FLAG-GO regimen was superior in optimal disease specific fusion transcript reduction at end of induction (p = .002), mid-consolidation (p < .01), and end of consolidation (p < .001) therapy. Induction/consolidation with FLAG-GO regimen results in better clinical outcomes in newly diagnosed patients with CBF-AML compared to FLAG-IDA and achieves deeper molecular clearance by qPCR assessment of the fusion transcripts.
Use of remdesivir in kidney transplant recipients with SARS-CoV-2 Omicron infection
Authors: Judit Cacho, David Nicolás, Marta Bodro, Elena Cuadrado-Payán, Verónica Torres-Jaramillo, Ángela Gonzalez-Rojas, Pedro Ventura-Aguiar, Enrique Montagud-Marrahi, Sabina Herrera, Veronica Rico, Frederic Cofàn, Frederic Oppenheimer, Ignacio Revuelta, Fritz Diekmann, David Cucchiari
Journal: Kidney International (2022)
Human T-Cell Lymphotropic Virus Type III Infection of the Central Nervous System
Authors: Mark H. Stoler
Journal: JAMA (1986)

Patients with the acquired immunodeficiency syndrome (AIDS) are subject to a spectrum of central nervous system (CNS) disorders. Recent evidence implicates the human T-cell lymphotropic virus type III (HTLV-III) in the pathogenesis of some of these illnesses, although the cells infected by the virus have yet to be identified. Using in situ hybridization, we examined brain tissue from two patients with AIDS encephalopathy for the presence of HTLV-III RNA. In both cases, viral RNA was detected and concentrated in, though not limited to, the white matter. The CNS cells most frequently infected included macrophages, pleomorphic microglia, and multinucleated giant cells. Less frequently, cells morphologically consistent with astrocytes, oligodendroglia, and rarely neurons were also infected. The findings strengthen the association of HTLV-III with the pathogenesis of AIDS encephalopathy. In situ hybridization can be applied to routinely prepared biopsy tissue in the diagnosis of HTLV-III infection of the CNS. (<i>JAMA</i>1986;256:2360-2364)
Spheroplexes: Hybrid PLGA-cationic lipid nanoparticles, for in vitro and oral delivery of siRNA
Authors: Danielle Campiol Arruda, Anne-Marie Lachagès, Hélène Demory, Guillaume Escriou, René Lai-Kuen, Pierre-Yves Dugas, Céline Hoffmann, Stéphanie Bessoles, Guillaume Sarrabayrouse, Angelo Malachias, Stéphanie Finet, Pedro Lana Gastelois, Waldemar Augusto de Almeida Macedo, Armando da Silva Cunha, Pascal Bigey, Virginie Escriou
Journal: Journal of Controlled Release (2022)
Ru(II)-modified TiO2 nanoparticles for hypoxia-adaptive photo-immunotherapy of oral squamous cell carcinoma
Authors: Jia-Ying Zhou, Wen-Jin Wang, Chen-Yu Zhang, Yu-Yi Ling, Xiao-Jing Hong, Qiao Su, Wu-Guo Li, Zong-Wan Mao, Bin Cheng, Cai-Ping Tan, Tong Wu
Journal: Biomaterials (2022)

The alternations in the hypoxic and immune microenvironment are closely related to the therapeutic effect and prognosis of oral squamous cell carcinoma (OSCC). Herein, a new nanocomposite, TiO2@[email protected] is constructed from a ruthenium-based photosensitizer (Ru) modified-TiO2 nanoparticles (NPs) loaded with siRNA of hypoxia-inducible factor-1α (HIF-1α). Under visible light irradiation, TiO2@[email protected] can elicit both Type I and Type II photodynamic effects, which causes lysosomal damage, HIF-1α gene silencing, and OSCC cell elimination efficiently. As a consequence of hypoxia relief and pyroptosis induction, TiO2@[email protected] reshapes the immune microenvironment by downregulation of key immunosuppressive factors, upregulation of immune cytokines, and activation of CD4+ and CD8+ T lymphocytes. Furthermore, patient-derived xenograft (PDX) and rat oral experimental carcinogenesis models prove that TiO2@[email protected]-mediated photodynamic therapy significantly inhibits the tumor growth and progression, and markedly enhances cancer immunity. In all, this study presents an effective hypoxia-adaptive photo-immunotherapeutic nanosystem with great potential for OSCC prevention and treatment.
A framework for falsifiable explanations of machine learning models with an application in computational pathology
Authors: David Schuhmacher, Stephanie Schörner, Claus Küpper, Frederik Großerueschkamp, Carlo Sternemann, Celine Lugnier, Anna-Lena Kraeft, Hendrik Jütte, Andrea Tannapfel, Anke Reinacher-Schick, Klaus Gerwert, Axel Mosig
Journal: Medical Image Analysis (2022)

In recent years, deep learning has been the key driver of breakthrough developments in computational pathology and other image based approaches that support medical diagnosis and treatment. The underlying neural networks as inherent black boxes lack transparency and are often accompanied by approaches to explain their output. However, formally defining explainability has been a notorious unsolved riddle. Here, we introduce a hypothesis-based framework for falsifiable explanations of machine learning models. A falsifiable explanation is a hypothesis that connects an intermediate space induced by the model with the sample from which the data originate. We instantiate this framework in a computational pathology setting using hyperspectral infrared microscopy. The intermediate space is an activation map, which is trained with an inductive bias to localize tumor. An explanation is constituted by hypothesizing that activation corresponds to tumor and associated structures, which we validate by histological staining as an independent secondary experiment.
European society of clinical microbiology and infectious diseases guidelines for coronavirus disease 2019: an update on treatment of patients with mild/moderate disease
Authors: Michele Bartoletti, Ozlem Azap, Aleksandra Barac, Linda Bussini, Onder Ergonul, Robert Krause, Alejandro Martin-Quiros, José Ramón Paño-Pardo, Nicholas Power, Marcella Sibani, Balint Gergely Szabo, Sotirios Tsiodras, Ines Zollner-Schwetz, Jesús Rodríguez-Baño
Journal: Clinical Microbiology and Infection (2022)
A 1000-year-old case of Klinefelter's syndrome diagnosed by integrating morphology, osteology, and genetics
Authors: Xavier Roca-Rada, Sofia Tereso, Adam B Rohrlach, André Brito, Matthew P Williams, Cláudia Umbelino, Francisco Curate, Ira W Deveson, Yassine Souilmi, António Amorim, Pedro C Carvalho, Bastien Llamas, João C Teixeira
Journal: The Lancet (2022)
Persistence, prevalence, and polymorphism of sequelae after COVID-19 in unvaccinated, young adults of the Swiss Armed Forces: a longitudinal, cohort study (LoCoMo)
Authors: Jeremy Werner Deuel, Elisa Lauria, Thibault Lovey, Sandrine Zweifel, Mara Isabella Meier, Roland Züst, Nejla Gültekin, Andreas Stettbacher, Patricia Schlagenhauf
Journal: The Lancet Infectious Diseases (2022)
Selected Articles from This Issue
Journal: Clinical Cancer Research (2021)

The addition of platinum to anthracycline-based neoadjuvant chemotherap. improves pathological responses in triple-negative breast cancer but also increases treatment toxicity. In the NeoSTOP randomized trial, Sharma and colleagues found that a carboplatin plus docetaxel (CbD) regimen yielded similar pathological response and survival rates as the anthracycline-containing regimen of carboplatin plus paclitaxel, followed by doxorubicin plus cyclophosphamide, but with a more favorable toxicity profile. The CbD regimen represents an effective alternative for patients who are not candidates for anthracyclines and may also serve as a good backbone for neoadjuvant de-escalation trials for triple-negative breast cancer.Combining checkpoint inhibitors with antiangiogenic agents holds promise for cancer treatment. In a prior phase I study, camrelizumab plus apatinib demonstrated encouraging activity in advanced hepatocellular carcinoma (HCC). To further study this combination, Xu and colleagues performed a phase II study of camrelizumab plus apatinib in patients with advanced HCC. The overall response rate was 34.3% in the first-line and 22.5% in the second-line setting. The 12-month survival rate was 74.7% and 68.2%, respectively. Serious adverse events were observed in 28.9% patients. Still, this work suggests that this combination warrants further study in patients with advanced HCC.Breast tumors with higher levels of cytotoxic T-cell infiltration have a better prognosis and response to preoperative chemotherapy. Oncolytic viruses such as talimogene laherparepvec (TVEC) cause selective lysis of tumor cells and trigger activation of antigen presenting cells to stimulate an antitumor immune response. Soliman and colleagues performed a phase I study of TVEC combined with neoadjuvant chemotherap. in patients with triple-negative breast cancer. This combination treatment led to a complete response in 55% of patients with manageable toxicity. Furthermore, evidence of decreased immunosuppression was observed. These results support further investigation of this regimen in further trials.Currently, effective strategies to monitor chimeric antigen receptor (CAR) T cells in tissue are lacking. Simonetta and colleagues assessed the utility of antibody-based PET (immunoPET) as a molecular imaging strategy to monitor CAR T cells in tissue. Inducible T-cell COStimulator (ICOS) was identified as a potential target for immunoPET. 89Zr-DFO-ICOS mAb PET-CT detected signal specifically in mice treated with CAR T cells. Importantly, ICOS-targeting antibodies did not affect CAR T-cell persistence or function. This work identifies ICOS-immunoPET imaging as a promising strategy for monitoring of CAR T-cell therapy; further study of this approach in a clinical setting is warranted.
Assessing the state of Medicaid coverage for gene and cell therapies
Authors: Diane Berry, Jennifer Wellman, Jeremy Allen, Christina Mayer
Journal: Molecular Therapy (2022)

Gene and cell therapies differ from small-molecule therapeutics in many ways, including the potential to treat the underlying cause of disease with a one-time dosing regimen. Those characteristics make gene and cell therapies highly valuable additions to the healthcare arsenal. However, one-time durable therapies currently come with associated upfront costs that can pose challenges to the US healthcare system, which is designed to support chronic treatments and care. The accessibility of such therapies to patients is of paramount importance to the American Society of Gene and Cell Therapy (ASGCT), which represents over 4,800 researchers, scientists, and clinicians in the field with the core mission of advancing the discovery and clinical application of genetic and cellular therapies to alleviate human disease.
Chromatin conformation of human oral epithelium can identify orofacial cleft missing functional variants
Authors: Yao Xiao, Shengbo Jiao, Miao He, Da Lin, Huanyan Zuo, Jiahao Han, Yonghua Sun, Gang Cao, Zhi Chen, Huan Liu
Journal: International Journal of Oral Science (2022)

Genome-wide association studies (GWASs) are the most widely used method to identify genetic risk loci associated with orofacial clefts (OFC). However, despite the increasing size of cohort, GWASs are still insufficient to detect all the heritability, suggesting there are more associations under the current stringent statistical threshold. In this study, we obtained an integrated epigenomic dataset based on the chromatin conformation of a human oral epithelial cell line (HIOEC) using RNA-seq, ATAC-seq, H3K27ac ChIP-seq, and DLO Hi-C. Presumably, this epigenomic dataset could reveal the missing functional variants located in the oral epithelial cell active enhancers/promoters along with their risk target genes, despite relatively less-stringent statistical association with OFC. Taken a non-syndromic cleft palate only (NSCPO) GWAS data of the Chinese Han population as an example, 3664 SNPs that cannot reach the strict significance threshold were subjected to this functional identification pipeline. In total, 254 potential risk SNPs residing in active cis-regulatory elements interacting with 1 718 promoters of oral epithelium-expressed genes were screened. Gapped k-mer machine learning based on enhancers interacting with epithelium-expressed genes along with in vivo and in vitro reporter assays were employed as functional validation. Among all the potential SNPs, we chose and confirmed that the risk alleles of rs560789 and rs174570 reduced the epithelial-specific enhancer activity by preventing the binding of transcription factors related to epithelial development. In summary, we established chromatin conformation datasets of human oral epithelial cells and provided a framework for testing and understanding how regulatory variants impart risk for clefts.
Single-cell transcriptomics reveals shared immunosuppressive landscapes of mouse and human neuroblastoma
Authors: Ana Costa, Cécile Thirant, Amira Kramdi, Cécile Pierre-Eugène, Caroline Louis-Brennetot, Orphée Blanchard, Didier Surdez, Nadege Gruel, Eve Lapouble, Gaëlle Pierron, Deborah Sitbon, Hervé Brisse, Arnaud Gauthier, Paul Fréneaux, Mylène Bohec, Virginie Raynal, Sylvain Baulande, Renaud Leclere, Gabriel Champenois, Andre Nicolas, Didier Meseure, Angela Bellini, Aurelien Marabelle, Birgit Geoerger, Fatima Mechta-Grigoriou, Gudrun Schleiermacher, Laurie Menger, Olivier Delattre, Isabelle Janoueix-Lerosey
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background High-risk neuroblastoma is a pediatric cancer with still a dismal prognosis, despite multimodal and intensive therapies. Tumor microenvironment represents a key component of the tumor ecosystem the complexity of which has to be accurately understood to define selective targeting opportunities, including immune-based therapies. Methods We combined various approaches including single-cell transcriptomics to dissect the tumor microenvironment of both a transgenic mouse neuroblastoma model and a cohort of 10 biopsies from neuroblastoma patients, either at diagnosis or at relapse. Features of related cells were validated by multicolor flow cytometry and functional assays. Results We show that the immune microenvironment of MYCN-driven mouse neuroblastoma is characterized by a low content of T cells, several phenotypes of macrophages and a population of cells expressing signatures of myeloid-derived suppressor cells (MDSCs) that are molecularly distinct from the various macrophage subsets. We document two cancer-associated fibroblasts (CAFs) subsets, one of which corresponding to CAF-S1, known to have immunosuppressive functions. Our data unravel a complex content in myeloid cells in patient tumors and further document a striking correspondence of the microenvironment populations between both mouse and human tumors. We show that mouse intratumor T cells exhibit increased expression of inhibitory receptors at the protein level. Consistently, T cells from patients are characterized by features of exhaustion, expressing inhibitory receptors and showing low expression of effector cytokines. We further functionally demonstrate that MDSCs isolated from mouse neuroblastoma have immunosuppressive properties, impairing the proliferation of T lymphocytes. Conclusions Our study demonstrates that neuroblastoma tumors have an immunocompromised microenvironment characterized by dysfunctional T cells and accumulation of immunosuppressive cells. Our work provides a new and precious data resource to better understand the neuroblastoma ecosystem and suggest novel therapeutic strategies, targeting both tumor cells and components of the microenvironment.
Risk Factors for Recurrent Nonsyncopal Falls
Authors: Michael C. Nevitt
Journal: JAMA (1989)

Falls are a major threat to the health of older persons. We evaluated potential risk factors for falls in 325 community-dwelling persons aged 60 years or older who had fallen during the previous year, then followed up weekly for 1 year to ascertain nonsyncopal falls and their consequences. Risk factors for having a single fall were few and relatively weak, but multiple falls were more predictable. In multivariate analyses, we found increased odds of two or more falls for persons who had difficulty standing up from a chair, difficulty performing a tandem walk, arthritis, Parkinson's disease, three or more falls during the previous year, and a fall with injury during the previous year, and for whites. The proportion of subjects with two or more falls per year increased from 0.10 for those with none or one of these risk factors to 0.69 for those with four or more risk factors. Among older persons with a history of a recent fall, the risk of multiple nonsyncopal falls can be predicted from a few simple questions and examinations. (<i>JAMA</i>. 1989;261:2663-2668)
Prevalence of and factors associated with osteoarthritis and pain in retired Olympians compared with the general population: part 1 – the lower limb
Authors: Debbie Palmer, Dale Cooper, Jackie L Whittaker, Carolyn Emery, Mark E Batt, Lars Engebretsen, Patrick Schamasch, Malav Shroff, Torbjørn Soligard, Kathrin Steffen, Richard Budgett
Journal: British Journal of Sports Medicine (2022)

Objectives This study aims (1) to determine the prevalence of lower limb osteoarthritis (OA) and pain in retired Olympians; (2) to identify factors associated with their occurrence and (3) to compare with a sample of the general population. Methods 3357 retired Olympians (median 44.7 years) and 1735 general population controls (40.5 years) completed a cross-sectional survey. The survey captured demographics, general health, self-reported physician-diagnosed OA, current joint/region pain and injury history (lasting &gt;1 month). Adjusted OR (aOR) compared retired Olympians with the general population. Results The prevalence of (any joint) OA in retired Olympians was 23.2% with the knee most affected (7.4%). Injury was associated with increased odds (aOR, 95% CI) of OA and pain in retired Olympians at the knee (OA=9.40, 6.90 to 12.79; pain=7.32, 5.77 to 9.28), hip (OA=14.30, 8.25 to 24.79; pain=9.76, 6.39 to 14.93) and ankle (OA=9.90, 5.05 to 19.41; pain=5.99, 3.84 to 9.34). Increasing age and obesity were also associated with knee OA and pain. While the odds of OA did not differ between Olympians and the general population, Olympians with prior knee and prior hip injury were more likely than controls with prior injury to experience knee (1.51, 1.03 to 2.21 (Olympians 22.0% vs controls 14.5%)) and hip OA (4.03, 1.10 to 14.85 (Olympians 19.1% vs Controls 11.5%)), respectively. Conclusions One in four retired Olympians reported physician-diagnosed OA, with injury associated with knee, hip and ankle OA and pain. Although overall OA odds did not differ, after adjustment for recognised risk factors Olympians were more likely to have knee and hip OA after injury than the general population, suggesting injury is an occupational risk factor for retired Olympians.